Project Summary/Abstract Genomic analyses are at the heart of both basic science efforts to elucidate the mechanisms of tumor etiology, evolution, heterogeneity, progression, metastasis, and relapse, and also translational efforts to personalize cancer treatment. Both efforts are major missions at MD Anderson Cancer Center, and for these studies, some of which require tailored sequencing approaches, a large number of investigators rely on the Sequencing and Microarray Facility (SMF), the institution's primary core facility for genomic analyses. Unfortunately, due to an ever increasing demand for sequencing, the SMF cannot keep up with demand. Prepared sequencing libraries wait in queue for almost four months before space is available on the SMF's sequencers. The SMF seeks to alleviate this backlog and to improve sequencing options for investigators by purchasing the most up-to-date, high throughput sequencer on the market, the Illumina NovaSeq6000. This instrument uses Illumina's proven SBS (sequence by synthesis) chemistry and combines the best features of their existing sequencers into a single instrument whose increased sequence generation rates, ability to simultaneously carry out different types of sequencing in different lanes of a flow cell, and reduced reagent cost will enable the SMF to provide investigators data in a more timely manner and also the ability to increase sequencing coverage and/or number of samples included in sequencing projects within project budgets. Major Users of the SMF are carrying out large epidemiologic studies that entail gene discovery phases in individuals with increased cancer risk, candidate gene replication phases, additional validation phases in other populations, and sequencing tumor DNA. For replication phases, PIs currently plan to use targeted gene panels for each study. The increased speed and lower costs of the NovaSeq6000 will allow them, instead, to carry out whole exome sequencing, enable them to share control exomes across projects and to use those data sets (to be deposited into dbGaP) in future studies. Thus the NovaSeq6000 will greatly expand the breadth and long-term impact of their studies and enhance resources for the scientific community at large. The research projects of other users (>100, a few of whom are highlighted) will also greatly benefit from the NovaSeq6000. These projects include those investigating cancer progression and metastasis, epigenetic reader proteins altered in cancers, the molecular basis of treatment resistance, epigenetic response to therapy, functional analyses of gene alterations, and the development and validation of approaches for using blood for early disease detection, monitoring of treatment, and relapse detection. Some projects use poor quality/low quantity analytes (FFPE, single cells, impure xenografts) and require customized protocols developed through close collaboration with the SMF. Thus investigators with a wide range of sequencing needs will greatly benefit from the reduced costs and faster sequence generation times of having a NovaSeq6000 in the SMF.